PI Vijay Gorantla
Co-I Joel Schumann, Kia Washington
Title Novel Strategies for Optic Neuroregeneration and Retinal Projection Reintegration after Ocular Trauma
Description: Background: The proposed research addresses multiple FY13 VRP TRA Focus Areas: Mitigation and treatment of traumatic ocular injuries, neuroprotection, axonal regeneration, and other reparative or restorative interventional strategies to prevent vision loss. Under normal conditions, damage to the optic nerve (ON) results in a permanent loss of vision due to the inability of retinal ganglion cells (RGCs), the projection neurons of the eye, to regenerate injured axons. This inability has also precluded the ambitious goal of transplanting a whole donor eye to restore vision in victims of devastating ocular injury, ischemic optic neuropathy, glaucoma, or macular degeneration. In recent years, however, there have been major experimental breakthroughs in promoting long distance ON regeneration and in refining surgical and immunomodulatory protocols in complex vascularized composite allotransplants (VCA). Similar to a hand or face transplant, a whole eyeball transplant (WET) is also a VCA, as it combined multiple tissue types. Our goal in the proposed work is to investigate, via a disruptive cross-disciplinary approach, the opportunities and challenges to vision restoration using translational strategies for ON neuroregeneration, RGC neuroprotection and ON reintegration into the brain, evaluated in a robust experimental model of WET.
Objective/Hypothesis: The overarching goal of this research is to restore vision following devastating damage to the eye and/or ON. Our central hypothesis is that targeted genetic interventions and/or treatment with neurotrophic factors and second messengers in the eye can promote extensive axonal regeneration and partially restore vision after acute ON injury. We believe that our data in rodent models of ON injury, as well as a robust WET model that will enable us to optimize perfusion, surgical approaches, viability and regenerative responses, will help us advance to our ultimate goal of neuro-anatomical integration and visual recovery.
Specific Aims: (1) Establish the time course/thresholds of donor eye viability and evaluate immunologic outcomes of WET; (2) Optimize strategies for ON regeneration and reintegration of retinal inputs in rodent models of ON crush and transection/repair; and (3) Implement a model of WET optimized for eye viability, neuroprotection of RGCs, ON axonal regeneration, and the restoration of neural connections between the eye and brain.
Study Design: Aim 1: We will investigate preservation strategies to optimize targeted interventions that prolong ocular tissue survival, primarily for RGCs and other retinal neurons (neuroprotection). We will determine timeto-transplant, temperature, neurotrophic and other survival strategies and their optimal application windows. We will optimize surgical approaches in WET including revascularization of posterior and anterior segments. We will evaluate the immunologic outcomes of WET in syngeneic and allogeneic settings. Primary measures include quantitation of RGC viability, tissue reperfusion, and evaluation of immunological markers. Aim 2: Based on prior studies showing a synergism of treatments that act via different molecular mechanisms, we will test the hypothesis that treatments that knock-down expression of growth-suppressive KLF family members, increase levels of the growth factors oncomodulin, CNTF and/or cAMP levels, activate certain signal-transduction pathways, overcome cell-extrinsic barriers to axon growth, and/or chelate particular cations, will lead to unprecedented levels of axon regeneration and to a partial recovery of visual function. Primary measures include quantitation of axon regeneration through the ON and into central visual target areas, RGC survival, and performance on 3 tests of visual function. Aim 3: We will combine the optimized neuroprotective and microsurgical approaches from Aim 1 with the optimized approaches to promote regeneration in Aim 2 in our rat WET model. At the anatomical level, we will quantify the ability of axons to extend though the ON, cross the optic chiasm, and reinnervate central brain structures. At the functional level, we will quantify performance on 3 tests of visual responsiveness.
Military Benefit: Between 2000 and 2010, 186,555 cases of combat ocular trauma (COT) were reported among deployed troops, not including those at sea, with 3% requiring hospitalization. In addition to direct COT, as many as 70% of severe and moderate TBI cases and 40% of mild TBI cases include some form of visual impairment. Such injuries prevent return to duty compromising years of training and expertise. More importantly, the functional limitations resulting from vision loss/dysfunction lead to significant personal, professional and psychosocial impairment. The projected costs to the economy of service members with eye injuries or vision impairment due to TBI is over $20 billion. WET could hold the potential for reversing devastating vision loss with no alternative treatment options. The proposed research could help pioneer technologies for vision restoration in COT and enable victims to reintegrate into mainstream life as “whole” individuals.
Source: Department of Defense Vision Research Program